CN102362855B - Itraconazole isomer oral liquid - Google Patents
Itraconazole isomer oral liquid Download PDFInfo
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- CN102362855B CN102362855B CN 201110339205 CN201110339205A CN102362855B CN 102362855 B CN102362855 B CN 102362855B CN 201110339205 CN201110339205 CN 201110339205 CN 201110339205 A CN201110339205 A CN 201110339205A CN 102362855 B CN102362855 B CN 102362855B
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- itraconazole
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- distilled water
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- hydroxypropyl cellulose
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- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical class O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 title claims abstract description 117
- 239000007788 liquid Substances 0.000 title claims abstract description 41
- 229960004130 itraconazole Drugs 0.000 claims abstract description 100
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
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- 239000003795 chemical substances by application Substances 0.000 description 7
- VHVPQPYKVGDNFY-ZPGVKDDISA-N itraconazole Chemical compound O=C1N(C(C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-ZPGVKDDISA-N 0.000 description 4
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- 229940063138 sporanox Drugs 0.000 description 4
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 3
- BQPPJGMMIYJVBR-UHFFFAOYSA-N (10S)-3c-Acetoxy-4.4.10r.13c.14t-pentamethyl-17c-((R)-1.5-dimethyl-hexen-(4)-yl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C BQPPJGMMIYJVBR-UHFFFAOYSA-N 0.000 description 2
- CHGIKSSZNBCNDW-UHFFFAOYSA-N (3beta,5alpha)-4,4-Dimethylcholesta-8,24-dien-3-ol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21 CHGIKSSZNBCNDW-UHFFFAOYSA-N 0.000 description 2
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- FPTJELQXIUUCEY-UHFFFAOYSA-N 3beta-Hydroxy-lanostan Natural products C1CC2C(C)(C)C(O)CCC2(C)C2C1C1(C)CCC(C(C)CCCC(C)C)C1(C)CC2 FPTJELQXIUUCEY-UHFFFAOYSA-N 0.000 description 2
- BKLIAINBCQPSOV-UHFFFAOYSA-N Gluanol Natural products CC(C)CC=CC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(O)C(C)(C)C4CC3 BKLIAINBCQPSOV-UHFFFAOYSA-N 0.000 description 2
- LOPKHWOTGJIQLC-UHFFFAOYSA-N Lanosterol Natural products CC(CCC=C(C)C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 LOPKHWOTGJIQLC-UHFFFAOYSA-N 0.000 description 2
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- QBSJHOGDIUQWTH-UHFFFAOYSA-N dihydrolanosterol Natural products CC(C)CCCC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 QBSJHOGDIUQWTH-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- -1 hydroxypropyl Chemical group 0.000 description 2
- CAHGCLMLTWQZNJ-RGEKOYMOSA-N lanosterol Chemical compound C([C@]12C)C[C@@H](O)C(C)(C)[C@H]1CCC1=C2CC[C@]2(C)[C@H]([C@H](CCC=C(C)C)C)CC[C@@]21C CAHGCLMLTWQZNJ-RGEKOYMOSA-N 0.000 description 2
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
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- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
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- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
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- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses itraconazole isomer oral liquid, which comprises itraconazole, cyclodextrin or derivative of cyclodextrin and other auxiliary materials, wherein itraconazole is 2S4R itraconazole. The solubility of the 2S4R itraconazole in an aqueous medium containing hydroxypropyl-beta-cyclodextrin is much higher than that of the racemic mixture of four isomers of itraconazole, namely under the condition of medicines at the same concentration, only a small amount of hydroxypropyl-beta-cyclodextrin is required as a solubilizer, so the consumption of hydroxypropyl-beta-cyclodextrin is reduced; thus, the clinic dose and administration period of the medicine are reduced, the clinic treatment effect is enhanced, and adverse reactions are reduced. In addition, because hydroxypropyl-beta-cyclodextrin is very expensive, the reduction of dose can reduce the production cost of the preparation. In the invention, the preparation which is prepared by using 2S4R itraconazole as the active ingredient requires much less hydroxypropyl-beta-cyclodextrin than the conventional itraconazole oral liquid and is suitable to be used as an angiogenesis inhibitor to treat various tumor diseases in clinic.
Description
Technical field:
The invention belongs to field of medicaments, be specifically related to a kind of isomer with itraconazole-2S4R itraconazole as the Itraconazole isomer oral liquid of the medicine of angiogenesis inhibiting.
Background technology:
Itraconazole or (±)-suitable-4-[4-[4-[4-[[2-(2, the 4-Dichlorobenzene base)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxane-4-yl] methoxyl group] phenyl]-the 1-piperazinyl] phenyl]-2,4-dihydro-2-(1-first propyl group)-3H-1,2,4-triazole-3-ketone, structure is shown in formula I, be US Patent No. 4267179 disclosed a kind of can oral, non-intestinal and local broad-spectrum antifungal chemical compound, trade name SPORANOX.Itraconazole is four diastereomers (two enantiomer to), have 1: 1: 1 of three chiral centres: 1 racemic mixture, correspond to 2S4R2 ' S, 2S4R2 ' R, 2R4S2 ' S, 2R4S2 ' R itraconazole, free alkali form and the pharmaceutically acceptable salt of the mixture of in 2S4R2 ' S, the 2S4R2 ' R isomer or two should broadly be explained and comprise in term " 2S4R itraconazole " when being used in hereinafter.For avoiding the adverse effect of mixture clinical practice, United States Patent (USP) the 5th, 474 discloses the method and composition of 2R4S curative effective of Itraconazole in curing local and whole body fungus, yeast and skin fungus infection for No. 997.China Patent Publication No.: 101711156, application number: 200880019020.6, denomination of invention: as the preparation method that discloses the 2S4R itraconazole in the isomeric compound of the chiral purity of the itraconazole of angiogenesis inhibitors and the agent of lanosterol 14A-demethyl enzymeinhibition.
Itraconazole dissolubility in aqueous medium is extremely low, and it is very difficult to be prepared into oral formulations, and the oral solution trade name that contains itraconazole of market sale is Sporanox.The concentration 10mg/ml of itraconazole in the oral administration solution, the pharmaceutic adjuvant that adds in the aqueous solution comprises HP-β-CD, propylene glycol, sorbitol, hydrochloric acid, sodium hydroxide, saccharin sodium and correctives.The purpose that adds HP-β-CD is to improve the water solublity of itraconazole by forming clathrate.United States Patent (USP) discloses a kind of oral administration solution prescription that does not contain cyclodextrin for No. 6340698, and by itraconazole, a kind of acid, one or more alcohol solvent compositions, wherein the alcohol solvent load is from 200 to 800mg/ml.The acid of using in an embodiment is the hydrochloric acid of concentration 4mg/ml, and the alcohol solvent is concentration 520mg/ml propylene glycol, also contains 70% sorbitol 660mg/ml in the solution; But this prescription of discovery does not subsequently have Sporanox solution-stabilized.United States Patent (USP) discloses a kind of improvement prescription No. 2007021438, has solved this solution instability problem, and the consumption that increases propylene glycol on the composition of prescription surpasses 800mg/ml, and the water content of solution reduces to below the 180mg/ml, has reduced simultaneously sour consumption.European patent also discloses a kind of oral administration solution prescription that does not contain HP-β-CD for No. 1698327, oral administration solution is comprised of itraconazole, propylene glycol, hydrochloric acid, sorbitol, saccharin sodium, correctives and sodium hydroxide, owing to add the stability that the 0.01-0.8% water-soluble cellulose has improved oral administration solution in the prescription.
The prescription HP-β-CD concentration of describing in Sporanox oral administration solution operation instructions is up to 40%, and the concentration of principal agent itraconazole only has 1%.The HP-β-CD oral administration safety is confirmed in the test of animal and human's body already, but Jiri and Pitha[J Pharm Sci, 1996; 85 (1): 96] do not have toxicity although propose HP-β-CD self, it can be unhealthful by increasing the absorption in gastrointestinal tract of lipophilic toxin and carcinogen.It is improper using excessive HP-β-CD, had better not be used in a large number oral.
Summary of the invention:
The purpose of this invention is to provide a kind of consumption that can reduce cyclodextrin, thereby improve clinical drug using dosage and medication cycle, increase clinical therapeutic efficacy, reduce untoward reaction, reduce production costs, the Itraconazole isomer oral liquid of good stability.
2S4R itraconazole and 2R4S itraconazole are non-mapping isomers, obviously has different physicochemical properties, the present invention found through experiments, the clathrate that the 2S4R itraconazole replaces itraconazole (four kinds of isomers) and HP-β-CD to prepare, in the situation that reduces the HP-β-CD consumption, still can greatly improve the solubility property of 2S4R itraconazole, thereby realize purpose of the present invention.
Itraconazole isomer oral liquid of the present invention comprises itraconazole, cyclodextrin or its derivant, and other adjuvants, it is characterized in that, described itraconazole is the 2S4R itraconazole.
Described cyclodextrin or its derivant refer to alpha-cyclodextrin or derivatives thereof, beta-schardinger dextrin-or derivatives thereof, gamma-cyclodextrin or derivatives thereof, most preferred cyclodextrin derivative is HP-β-CD, wherein M.S. contains and is less than 1.5% unsubstituted beta-schardinger dextrin-in 0.35 to 0.50 scope.
Described other adjuvants comprise alcohol cosolvent, acidic aqueous medium, water-soluble cellulose, sweeting agent, correctives, pH regulator liquid and distilled water.
Described alcohol cosolvent includes but not limited to ethanol, propylene glycol, glycerol or Polyethylene Glycol, be preferably propylene glycol, concentration is 10% (v/v), and the existence of alcohol cosolvent can greatly promote the formation of drug-cyclodextrin clathrate, greatly shortens preparation time.
Described acidic aqueous medium can adopt a kind of strong acid, and example hydrochloric acid in preparation process, is adjusted to pH 2 ± 0.1 and can obtains the best, stable effect.
Described water-soluble cellulose includes but not limited to hydroxypropyl cellulose, hydroxypropyl emthylcellulose, is preferably hydroxypropyl cellulose, and concentration is 0.05% (w/v), can increase the stability of oral administration solution.
Described sweeting agent comprises one or more, as: glucide, saccharin sodium or calcium salt, sorbitol, mannitol, fructose, sucrose, maltose, dextrinose, glucose, Xylitol, caramel, Mel.
Described correctives can be but be not limited to cherry-flavored, Fructus Fragariae Ananssae flavor, chocolate flavoured, mint flavored, caramel.Sweeting agent and correctives mainly are in order to improve the mouthfeel of solution.
Described pH regulator liquid can be selected NaOH solution, and the pH value of regulating the itraconazole oral administration solution is about 2.0.
Preferably, described Itraconazole isomer oral liquid, formed by following composition: 2S4R itraconazole 1～4% (w/v), HP-β-CD 10～40% (w/v), propylene glycol 10～40% (v/v), hydroxypropyl cellulose 0.01～0.1% (w/v), an amount of strong acid, pH regulator liquid, sweeting agent and correctives, all the other are water.
Further preferred, described Itraconazole isomer oral liquid, formed by following composition: 2S4R itraconazole 1% (w/v), HP-β-CD 25% (w/v), propylene glycol 10% (v/v), 70% sorbitol 20% (v/v), hydrochloric acid 0.38% (v/v), hydroxypropyl cellulose 0.05% (w/v), saccharin sodium 0.06% (W/V), correctives 0.1%, an amount of NaOH, pH2.0 ± 0.1, all the other are water.
Term " 2S4R itraconazole " being interpreted as in the present invention: the free alkali form or the pharmaceutically acceptable salt that comprise the mixture of in 2S4R2 ' S, the isomer of 2S4R2 ' R itraconazole or two.Preferred 2S4R itraconazole is 2S4R2 ' S, 1: 1 mixture of 2S4R2 ' R itraconazole.
2S4R itraconazole of the present invention can adopt China Patent Publication No.: 101711156, application number: 200880019020.6, denomination of invention: make as disclosed preparation method in the isomeric compound of the chiral purity of the itraconazole of angiogenesis inhibitors and the agent of lanosterol 14A-demethyl enzymeinhibition.
Itraconazole isomer oral liquid of the present invention can just change itraconazole into the 2S4R itraconazole according to the preparation method preparation of the itraconazole oral administration solution of routine, and the amount of cyclodextrin is adjusted according to the dissolubility of 2S4R itraconazole accordingly.
The effect experiment:
Itraconazole (mixture of four kinds of isomers) and 2S4R itraconazole (2S4R2 ' S, 1: 1 mixture of 2S4R2 ' R itraconazole) the dissolubility test in HP-β-CD solution:
Weigh respectively 0,15,20,30, the 40g HP-β-CD adds dissolved in distilled water and is diluted to 100ml, getting respectively itraconazole or 2S4R itraconazole joins in the above-mentioned solution that contains HP-β-CD in right amount, make saturated solution, placement is spent the night.Get supernatant with 0.4 μ m membrane filtration, measuring trap at wavelength 255nm (quantitatively dilutes solution in case of necessity, make the measured value of solution absorption degree less than 0.8), the content (g) of itraconazole or 2S4R itraconazole in the calculating supernatant, the result who records is as shown in table 1:
Table 1: itraconazole and the 2S4R itraconazole dissolubility in variable concentrations HP-β-CD solution
Annotate: N.D represents the detection range that concentration is lower than detector.
As can be seen from Table 1, the dissolubility of 2S4R itraconazole in containing the aqueous medium of HP-β-CD is higher than the racemic mixture of four kinds of isomers of itraconazole far away, also be under the drug condition of same concentrations, only need the HP-β-CD of small amount as solubilizing agent, therefore reduce the consumption of HP-β-CD, thereby improve clinical drug using dosage and medication cycle, increase clinical therapeutic efficacy, reduce untoward reaction, and because HP-β-CD is expensive, reduce the production cost that consumption also can reduce preparation.
Therefore, the present invention utilizes the 2S4R itraconazole as active component, and the HP-β-CD that the preparation of preparation need to use than existing itraconazole oral administration solution reduces a lot, is applicable to as the various tumor diseases of angiogenesis inhibitor clinical treatment.
The specific embodiment:
Following examples are to further specify of the present invention, rather than limitation of the present invention.
Embodiment 1:
Preparation 1000ml 2S4R itraconazole concentration is the oral administration solution of 15% (w/v), and it contains following composition:
2S4R itraconazole 150g, HP-β-CD 400g, propylene glycol 100ml, 70% sorbitol 200ml, hydrochloric acid 3.8ml, saccharin sodium 0.6g, hydroxypropyl cellulose 0.5g, cherry-flavored correctives 1g, benefit distilled water are to 1000ml.
Its preparation method: at first in the 200ml distilled water, add 0.5g hydroxypropyl cellulose, stirring and dissolving; The concentrated hydrochloric acid that in the 100ml propylene glycol, adds in addition 3.8ml, slight fever also stirs, and the 2S4R itraconazole that adds 150g is stirred to homogeneous phase.Other gets a container, the HP-β-CD of 400g is added stirring and dissolving in the 400ml distilled water, under constantly stirring, slowly join in the cyclodextrin solution above-mentioned 2S4R itraconazole propylene glycol acid solution, obtain the inclusion complex in solution of 2S4R itraconazole, add again the 200ml sorbitol solution, 0.6g saccharin sodium, the 1g correctives, adding at last hydroxypropyl cellulose solution stirs, and regulate pH to 2.0 with the 10mol/L sodium hydroxide solution, the solution that obtains to 1000ml, filters the oral administration solution that obtains the 2S4R itraconazole with distilled water diluting
With in the poly-vial of every bottle of 250ml volume packing, liquid level needs remaining a small amount of gas in vial after filtering, and preferably noble gas such as nitrogen-sealed, will be conducive to 25 ℃ of lower long preservation of oral liquid, and oral liquid answers the lucifuge cannot be freezing.
Embodiment 2
Preparation 1000ml 2S4R itraconazole concentration is the oral administration solution of 5% (w/v), and it contains following composition:
2S4R itraconazole 50g, HP-β-CD 300g, propylene glycol 200ml, 70% sorbitol 200ml, hydrochloric acid 3.8ml, saccharin sodium 0.6g, hydroxypropyl cellulose 0.1g, caramel correctives 1g, adding distil water is to 1000ml again.
Its preparation method: at first in the 200ml distilled water, add 0.1g hydroxypropyl cellulose, stirring and dissolving; The concentrated hydrochloric acid that in the 200ml propylene glycol, adds in addition 3.8ml, slight fever also stirs, and the 2S4R itraconazole that adds 50g is stirred to homogeneous phase.Other gets a container, the HP-β-CD of 300g is added stirring and dissolving in the 400ml distilled water, under constantly stirring, slowly join in the cyclodextrin solution above-mentioned 2S4R itraconazole propylene glycol acid solution, obtain the inclusion complex in solution of 2S4R itraconazole, add again the 200ml sorbitol solution, 0.6g saccharin sodium, the 1g correctives, adding at last hydroxypropyl cellulose solution stirs, and regulate pH to 2.0 with the 10mol/L sodium hydroxide solution, the solution that obtains, filters and obtains 2S4R itraconazole oral administration solution to 1000ml with distilled water diluting.
With in the poly-vial of every bottle of 250ml volume packing, liquid level needs remaining a small amount of gas in vial after filtering, and preferably noble gas such as nitrogen-sealed, will be conducive to 25 ℃ of lower long preservation of oral liquid, and oral liquid answers the lucifuge cannot be freezing.
Embodiment 3
Preparation 1000ml 2S4R itraconazole concentration is the oral administration solution of 3% (w/v), and it contains following composition:
2S4R itraconazole isomer 30g, HP-β-CD 200g, propylene glycol 200ml, 70% sorbitol 200ml, hydrochloric acid 3.8ml, saccharin sodium 0.6g, hydroxypropyl cellulose 1g, cherry-flavored correctives 1g, adding distil water is to 1000ml again.
Its preparation method: at first in the 300ml distilled water, add 1g hydroxypropyl cellulose, stirring and dissolving; The concentrated hydrochloric acid that in the 200ml propylene glycol, adds in addition 3.8ml, slight fever also stirs, and the 2S4R itraconazole that adds 30g is stirred to homogeneous phase.Other gets a container, the HP-β-CD of 200g is added stirring and dissolving in the 200ml distilled water, under constantly stirring, slowly join in the cyclodextrin solution above-mentioned 2S4R itraconazole propylene glycol acid solution, obtain the inclusion complex in solution of 2S4R itraconazole, add again the 200ml sorbitol solution, 0.6g saccharin sodium, the 1g correctives, adding at last hydroxypropyl cellulose solution stirs, and regulate pH to 2.0 with the 10mol/L sodium hydroxide solution, the solution that obtains, filters and obtains 2S4R itraconazole oral administration solution to 1000ml with distilled water diluting.
With in the poly-vial of every bottle of 250ml volume packing, liquid level needs remaining a small amount of gas in vial after filtering, and preferably noble gas such as nitrogen-sealed, will be conducive to 25 ℃ of lower long preservation of oral liquid, and oral liquid answers the lucifuge cannot be freezing.
Embodiment 4
Preparation 1000ml 2S4R itraconazole concentration is the oral administration solution of 1% (w/v), and it contains following composition:
The cherry-flavored correctives of 2S4R itraconazole isomer 10g, HP-β-CD 250g, propylene glycol 100ml, 70% sorbitol 200ml, hydrochloric acid 3.8ml, 0.6g saccharin sodium, 0.5g hydroxypropyl cellulose, 1g, adding distil water is to 1000ml again.
Its preparation method: at first in the 100ml distilled water, add 0.5g hydroxypropyl cellulose, stirring and dissolving; The concentrated hydrochloric acid that in the 100ml propylene glycol, adds in addition 3.8ml, slight fever also stirs, and the 2S4R itraconazole that adds 10g is stirred to homogeneous phase.Other gets a container, the HP-β-CD of 250g is added stirring and dissolving in the 200ml distilled water, under constantly stirring, slowly join in the cyclodextrin solution above-mentioned 2S4R itraconazole propylene glycol acid solution, obtain the inclusion complex in solution of 2S4R itraconazole, add again the 200ml sorbitol solution, 0.6g saccharin sodium, the 1g correctives, adding at last hydroxypropyl cellulose solution stirs, and regulate pH to 2.0 with the 10mol/L sodium hydroxide solution, the solution that obtains, filters and obtains 2S4R itraconazole oral administration solution to 1000ml with distilled water diluting.
With in the poly-vial of every bottle of 250ml volume packing, liquid level needs remaining a small amount of gas in vial after filtering, and preferably noble gas such as nitrogen-sealed, will be conducive to 25 ℃ of lower long preservation of oral liquid, and oral liquid answers the lucifuge cannot be freezing.
Claims (4)
1. Itraconazole isomer oral liquid, it is characterized in that, preparation 1000ml is take the oral administration solution of w/v 2S4R itraconazole concentration as 15%, it contains following composition: 2S4R itraconazole 150g, HP-β-CD 400g, propylene glycol 100ml, 70% sorbitol 200ml, and hydrochloric acid 3.8ml, saccharin sodium 0.6g, hydroxypropyl cellulose 0.5g, cherry-flavored correctives 1g, benefit distilled water are to 1000ml; Its preparation method: at first in the 200ml distilled water, add 0.5g hydroxypropyl cellulose, stirring and dissolving; The concentrated hydrochloric acid that in the 100ml propylene glycol, adds in addition 3.8ml, slight fever also stirs, and the 2S4R itraconazole that adds 150g is stirred to homogeneous phase; Other gets a container, the HP-β-CD of 400g is added stirring and dissolving in the 400ml distilled water, under constantly stirring, slowly join in the cyclodextrin solution above-mentioned 2S4R itraconazole propylene glycol acid solution, obtain the inclusion complex in solution of 2S4R itraconazole, add again the 200ml sorbitol solution, 0.6g saccharin sodium, the 1g correctives, adding at last hydroxypropyl cellulose solution stirs, and regulate pH to 2.0 with the 10mol/L sodium hydroxide solution, the solution that obtains to 1000ml, filters the oral administration solution that obtains the 2S4R itraconazole with distilled water diluting; With in the poly-vial of every bottle of 250ml volume packing, liquid level needs remaining a small amount of nitrogen-sealed in vial, will be conducive to 25 ℃ of lower long preservation of oral liquid after filtering, and oral liquid answers the lucifuge cannot be freezing.
2. Itraconazole isomer oral liquid, it is characterized in that, preparation 1000ml is take the oral administration solution of w/v 2S4R itraconazole concentration as 5%, it contains following composition: 2S4R itraconazole 50g, HP-β-CD 300g, propylene glycol 200ml, 70% sorbitol 200ml, hydrochloric acid 3.8ml, saccharin sodium 0.6g, hydroxypropyl cellulose 0.1g, caramel correctives 1g, and adding distil water is to 1000ml again; Its preparation method: at first in the 200ml distilled water, add 0.1g hydroxypropyl cellulose, stirring and dissolving; The concentrated hydrochloric acid that in the 200ml propylene glycol, adds in addition 3.8ml, slight fever also stirs, and the 2S4R itraconazole that adds 50g is stirred to homogeneous phase; Other gets a container, the HP-β-CD of 300g is added stirring and dissolving in the 400ml distilled water, under constantly stirring, slowly join in the cyclodextrin solution above-mentioned 2S4R itraconazole propylene glycol acid solution, obtain the inclusion complex in solution of 2S4R itraconazole, add again the 200ml sorbitol solution, 0.6g saccharin sodium, the 1g correctives, adding at last hydroxypropyl cellulose solution stirs, and regulate pH to 2.0 with the 10mol/L sodium hydroxide solution, the solution that obtains, filters and obtains 2S4R itraconazole oral administration solution to 1000ml with distilled water diluting; With in the poly-vial of every bottle of 250ml volume packing, liquid level needs remaining a small amount of nitrogen-sealed in vial, will be conducive to 25 ℃ of lower long preservation of oral liquid after filtering, and oral liquid answers the lucifuge cannot be freezing.
3. Itraconazole isomer oral liquid, it is characterized in that, preparation 1000ml is take the oral administration solution of w/v 2S4R itraconazole concentration as 3%, it contains following composition: 2S4R itraconazole isomer 30g, HP-β-CD 200g, propylene glycol 200ml, 70% sorbitol 200ml, hydrochloric acid 3.8ml, saccharin sodium 0.6g, hydroxypropyl cellulose 1g, cherry-flavored correctives 1g, adding distil water is to 1000ml again; Its preparation method: at first in the 300ml distilled water, add 1g hydroxypropyl cellulose, stirring and dissolving; The concentrated hydrochloric acid that in the 200ml propylene glycol, adds in addition 3.8ml, slight fever also stirs, and the 2S4R itraconazole that adds 30g is stirred to homogeneous phase; Other gets a container, the HP-β-CD of 200g is added stirring and dissolving in the 200ml distilled water, under constantly stirring, slowly join in the cyclodextrin solution above-mentioned 2S4R itraconazole propylene glycol acid solution, obtain the inclusion complex in solution of 2S4R itraconazole, add again the 200ml sorbitol solution, 0.6g saccharin sodium, the 1g correctives, adding at last hydroxypropyl cellulose solution stirs, and regulate pH to 2.0 with the 10mol/L sodium hydroxide solution, the solution that obtains, filters and obtains 2S4R itraconazole oral administration solution to 1000ml with distilled water diluting; With in the poly-vial of every bottle of 250ml volume packing, liquid level needs remaining a small amount of nitrogen-sealed in vial, will be conducive to 25 ℃ of lower long preservation of oral liquid after filtering, and oral liquid answers the lucifuge cannot be freezing.
4. Itraconazole isomer oral liquid, it is characterized in that, preparation 1000ml is take the oral administration solution of w/v 2S4R itraconazole concentration as 1%, it contains following composition: the cherry-flavored correctives of 2S4R itraconazole isomer 10g, HP-β-CD 250g, propylene glycol 100ml, 70% sorbitol 200ml, hydrochloric acid 3.8ml, 0.6g saccharin sodium, 0.5g hydroxypropyl cellulose, 1g, and adding distil water is to 1000ml again; Its preparation method: at first in the 100ml distilled water, add 0.5g hydroxypropyl cellulose, stirring and dissolving; The concentrated hydrochloric acid that in the 100ml propylene glycol, adds in addition 3.8ml, slight fever also stirs, and the 2S4R itraconazole that adds 10g is stirred to homogeneous phase; Other gets a container, the HP-β-CD of 250g is added stirring and dissolving in the 200ml distilled water, under constantly stirring, slowly join in the cyclodextrin solution above-mentioned 2S4R itraconazole propylene glycol acid solution, obtain the inclusion complex in solution of 2S4R itraconazole, add again the 200ml sorbitol solution, 0.6g saccharin sodium, the 1g correctives, adding at last hydroxypropyl cellulose solution stirs, and regulate pH to 2.0 with the 10mol/L sodium hydroxide solution, the solution that obtains, filters and obtains 2S4R itraconazole oral administration solution to 1000ml with distilled water diluting; With in the poly-vial of every bottle of 250ml volume packing, liquid level needs remaining a small amount of nitrogen-sealed in vial, will be conducive to 25 ℃ of lower long preservation of oral liquid after filtering, and oral liquid answers the lucifuge cannot be freezing.
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| 伊曲康唑制剂的临床应用;孙黎等;《医药导报》;20020228;第21卷(第2期);第99－101页 * |
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